The authors characterized human immunodeficiency virus (HIV) and hepatitis C virus (HCV) incidence and prospective changes in self-reported risk behavior over 2 years among 1,158 injection drug users (IDUs) recruited in Chennai, India, in 2005-2006. At baseline, HIV prevalence was 25.3%, and HCV prevalence was 54.5%. Seropositive persons with prevalent HIV infection were used to estimate baseline HIV incidence by means of the Calypte HIV-1 BED Incidence EIA (Calypte Biomedical Corporation, Portland, Oregon). Longitudinal HIV and HCV incidence were measured among 865 HIV-negative IDUs and 519 HCV antibody-negative IDUs followed semiannually for 2 years. Participants received pre- and posttest risk reduction counseling at each visit. Estimated HIV incidence at baseline was 2.95 per 100 person-years (95% confidence interval (CI): 1.21, 4.69) by BED assay; observed HIV incidence over 1,262 person-years was 0.48 per 100 person-years (95% CI: 0.17, 1.03). HCV incidence over 645 person-years was 1.71 per 100 person-years (95% CI: 0.85, 3.03). Self-reported risk behaviors declined significantly over time, from 100% of participants reporting drug injection at baseline to 11% at 24 months. In this cohort with high HIV and HCV prevalence at enrollment, the authors observed low incidence and declining self-reported risk behavior over time. While no formal intervention was administered, these findings highlight the potential impact of voluntary counseling and testing in a high-risk cohort.